Biomedical Engineering Reference
In-Depth Information
rationale for the development of vector-based strategies, in which the thera-
peutic agent is delivered as a conjugate with a transport vector.
6.1.2.1 Receptor-mediated transcytosis
Large molecules which are necessary for the normal function of the brain
are delivered to the brain by specific receptors. These receptors are highly
expressed on the endothelial cells forming the BBB. In this process, the re-
quired physical characteristics are the endocytosis at the luminal (blood)
side after receptor-ligand binding, the movement through the endothelial
cytoplasm, and the exocytosis of the drug or ligand-attached drug or cargo
at the abluminal (brain) side. The endosomal/lysosomal systems, can poten-
tially degrade drug molecules, therapeutic protein and peptides and genetic
materials. The physiologic approach comprises targeting these receptors at
the BBB by specific ligands, modified ligands, and antibodies. Therapeutic
compounds are able to cross the BBB after association/conjugation to these
specific ligands. Receptor-mediated transcytosis has been demonstrated for
transferrin, insulin, insulin-like growth factors (IGF-1 and IGF-2), leptin,
and the low-density lipoprotein receptor-related protein (LRP).
Transferrin receptor (TR) is a transmembrane glycoprotein. The TR
is also expressed on hepatocytes, erythrocytes, intestinal cells, monocytes,
choroid plexus epithelial cells, neurons, and endothelial cells of the BBB.
The TR mediates cellular uptake of iron bound to transferrin. Drug tar-
geting to the TR can be achieved by using the endogenous ligand trans-
ferrin, or by using antibodies directed against the TR. Cationic liposomes
coupled with transferrin caused a significant enhancement of luciferase
gene expression activity in C6 glioma cells, primary hippocampal neurons
and primary cortical neurons [205]. The binding of the antibody to TR
enables it to penetrate the BBB. Ulbrich et al. [206] studied human seru-
malbumin (HAS) NPs with covalently coupled transferring, or transferrin
receptor monoclonal antibodies (OX26 or R17-217), for brain delivery of
loperamide. Results showed that significant anti-nociceptive effects were de-
tected with loperamide-loaded HAS NPs with covalently bound transfer-
ring of the OX20 or R17-217 antibodies. In a recent study van Rooy et al.
[207], demonstrated that different targeting ligands, R17-217 (against TfR)
showed a significant enhanced brain uptake of liposomes in vivo. Using the
brain capillary depletion method, the authors determined the uptake of 3H-
labelled liposomes in brain capillaries and found R17-217 liposomes were
10 times higher than un-targeted liposomes, suggesting that the high mo-
lecular weight and high affinity for the receptor may have contributed to its
strong brain targeting ability [165].
The insulin receptor (IR) is a large protein having a molecular weight
of 300 kDa. A novel study reports that a genetically engineered human/
mouse chimeric form of the human insulin receptor monoclonal antibody
(HIRMAb) in an adult Rhesus monkey, has showed that humanized
